The long-term objective of this application is to gain insight into the mechanisms of innate immunity to microbes in skin. The innate immune system must rapidly recognize microbial pathogens and trigger direct host antimicrobial response to limit the infection, yet the activation of the innate immune system also results in inflammation and tissue injury that characterize the clinical manifestations of human disease. This double- edged sword of innate immunity is clearly evident in acne vulgaris in which innate immune cells mount an antimicrobial response to P. acnes, but also induce an inflammatory response mediated by release of cytokines and matrix metalloproteinases (MMPs) that contribute to clinical disease. By investigating the role of the innate immune response in acne, our laboratory has elucidated several novel pathways relevant to clinical disease: i) P. acnes induces the differentiation of monocytes into macrophages with enhanced phagocytosis and antimicrobial activity, ii) P. acnes induces the production of vitamin D receptor-dependent antimicrobial peptide, cathelicidin, in human monocytes, iii) P. acnes induces inflammatory cytokines and MMP9 via toll-like receptor 2-dependent mechanism, iv) all-trans retinoic acid (ATRA) enhances the differentiation of monocytes into CD209+ macrophages and v) ATRA down-regulates TLR2 expression and function by inhibiting P. acnes- induced cytokine production in monocytes. Based on this work, we propose to extend these findings by investigating the differential innate immune responses, antimicrobial vs. inflammatory, to P. acnes in vitro and in vivo. The goal of these studies is to identify mechanistic pathways that differentially regulate the antimicrobial vs. inflammatory responses. It is anticipated that these pathways can be targeted by therapeutic intervention to maximize clinical efficacy while minimizing inflammation and tissue injury in patients with acne. Our proposed experiments should lead to novel avenues of immunologic intervention in acne as well as other cutaneous inflammatory and infectious diseases. PUBLIC HEALTH RELEVANCE: Our application has a significant implication in public health since acne affects the majority of population at some point in their lifetime yet due to limited research in this common skin disease, the pathogenesis is still not clear. In addition, given the restrictions placed on the use of oral retinoids as well as the development of antibiotic- resistant strains of P. acnes, research is needed to improve therapy. Our study will investigate the mechanisms by which P. acnes induces the double-edged sword of the innate immune system, antimicrobial and inflammation, which should provide insight into mechanisms of host defense and tissue injury in skin, leading to novel avenues of immunologic intervention not only in acne but in other cutaneous inflammatory and infectious diseases in general.